Signal transduction is the general process by which cells respond to extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.) through a cascade of biochemical reactions that begins with the binding of the signal molecule to a cell membrane receptor and ends with the activation of an intracellular target molecule. This process regulates all types of cell functions including cell proliferation, differentiation, and gene transcription.
One important pathway in this process is the G-protein signaling pathway. In this pathway, receptors on the cell surface are coupled to a protein (G-protein) on the plasma membrane of the cell which becomes activated, when the receptor is occupied, by binding to the molecule GTP. This in turn leads to the production of the second messenger molecule, cyclic-AMP, that controls the phosphorylation and activation of many intracellular proteins. The G-protein is a critical regulator of the pathway by virtue of the fact that GTPase activity in the G-protein eventually hydrolyzes the bound GTP to GDP, restoring the protein to its inactive state. Thus the G-protein contains a built-in deactivation mechanism for the signaling process.
Recently, a second regulatory mechanism has been discovered for the G-protein signaling pathway that involves a family of mammalian gene products termed regulators of G-protein signaling, or RGS (Druey, K. M. et al. (1996) Nature 379: 742-746). These proteins negatively regulate the G-protein pathway at a point upstream or at the level of the G-protein by an as yet unknown mechanism. Some 15 members of the RGS family have thus far been identified.
The first RGS family member BL34(RGS1) was found in activated B-lymphocytes associated with chronic lymphocytic leukemia. RGS1 inhibits the activation of MAP kinase, a G-protein mediated event, which is induced by the binding of platelet-activating factor to a B-cell receptor. RGS2 (GOS8) was likewise found in lectin stimulated peripheral blood mononuclear cells. Sequence similarities were noted between RSG2 and various genes involved in the immune system, in the regulation of retroviruses, and suppression of oncogenes (Siderovski D. P. et al. (1994) DNA Cell Biol. 13(2): 125-147).
These and other RGS family members are related structurally through similarities in a roughly 120 amino acid region termed the RGS domain, and functionally by their ability to inhibit the interleukin (cytokine) induction of MAP kinase in cultured mammalian 293T cells (Druey et al., supra).
It is proposed that RGS proteins inhibit G-protein function by direct binding to the protein and that individual RGS proteins preferentially regulate specific G-proteins and G-protein signaling pathways in the cells and tissues in which they are expressed. The discovery of a new RGS protein is useful because it provides another pathway for G-protein regulation. In particular, the new RGS may provide a means for treating conditions associated with uncontrolled cell signaling including cancer, inflammation and disorders of the sympathetic nervous system.